Gammadelta T cells represent a unique subset of T cells that bridge innate and adaptive immunity by recognizing self and foreign nonpeptide antigens. In addition to their role in microbial immunity, there is strong evidence that human gammadelta T cells help regulate B cell malignancies such as non-Hodgkin's lymphoma (NHL) and multiple myeloma. Supporting this hypothesis, gammadelta? T cells expand in some patients with lymphoid malignancies to up to 42% of circulating T cells. Human Vgamma2Vdelta2 T cells recognize and kill a subset of NHLs and multiple myelomas. Vgamma2Vdelta2 T cells can provide immunity for NHL in a SCID mouse model. Moreover, immunotherapy of lymphoma patients with synthetic bisphosphonate antigens and IL-2 to stimulate Vgamma2Vdelta2 T cells shows promise since it resulted in partial remissions or stable disease in 4 of 5 patients that had Vgamma2Vdelta2 T cell proliferation. For this immunotherapy to be more effective, basic knowledge is needed about how Vgamma2Vdelta2 T cells respond to nonpeptide antigens, how gammadelta T cell memory develops, and what are the most effective ways to stimulate Vgamma2Vdelta2 T cells in vivo. We have found that adult Vgamma2Vdelta2 T cells are almost exclusively memory cells that are divided into 3 subsets, central memory, effector memory, and effector CD45RA+memory. Each subset has distinctive functional and migratory properties. We find that central memory Vgamma2Vdelta2 T cells are deleted or anergized in multiple myeloma patients that have been treated with the bisphosphonate, zolendronate, in the absence of rIL-2. Here we propose to test the hypothesis that Vgamma2Vdelta2 T cells recognize and kill a subset of malignant B cells that have elevated levels of IPP and NKG2D ligands. Activating V?2V?2 T cells with nonpeptide antigens and growth factors can lead to the elimination or stabilization of disease in patients with B cell malignancies. In Aim 1, we will correlate expression of NKG2D ligands with the ability of malignant B cells to stimulate Vgamma2Vdelta2 T cells. In Aim 2, we will test different memory subsets of Vgamma2Vdelta2 T cells for their ability to control lymphomas in adaptive immunotherapy in an in vivo SCID-beige mouse model. In Aim 3, we will test vaccination protocols using bisphosphonate antigens, adjuvants, and growth cytokines in monkeys for their ability to stimulate Vgamma2Vdelta2 T cells. These studies will help to elucidate the molecular basis of Vgamma2Vdelta2T cell recognition of malignant B cells and the function of memory gammadelta T cell subsets in lymphoma immunity and will provide crucial information on optimising immunotherapy with gammadelta T cells.